A Facile Protocol for C(sp²)-C(sp³) Bond Formation Reactions Toward Functionalized E3 Ligase Ligands

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Targeted protein degradation (TPD) relies on E3 ligase ligands.
• Existing methods often use C(sp2)-N bonds, limiting chemical diversity.
• Understanding linker effects on ligand properties is crucial for TPD efficacy.

Purpose of the Study:

• To develop novel cereblon (CRBN) E3 ligase ligands using a C(sp2)-C(sp3) bond-forming strategy.
• To investigate the impact of linker attachment and bond types on ligand stability, binding affinity, and degradation performance.
• To explore new chemical space for TPD applications beyond traditional C(sp2)-N connections.

Main Methods:

• Employed a decarboxylative cross-coupling reaction using N-hydroxyphthalimide (NHP) esters and aryl bromides.
• Synthesized and characterized novel CRBN binders and their derivatives.
• Assessed binding affinity, aqueous solubility, microsomal stability, and degradation of off-targets.

Main Results:

• Developed a versatile C(sp2)-C(sp3) bond-forming method for CRBN ligand synthesis.
• Demonstrated that C(sp2)-C(sp3) linkages improve physicochemical stability and binding affinity.
• Successfully generated potent BRD4-targeting PROTACs and GSPT1-targeting molecular glues using the new ligands.

Conclusions:

• The C(sp2)-C(sp3) bond strategy significantly expands the accessible chemical space for TPD ligands.
• This synthetic innovation allows fine-tuning of PROTAC characteristics and unlocks novel degrader chemotypes.
• The findings underscore the importance of synthetic methodology in advancing TPD applications.